A phase 1, multicenter, open-label, first-in-human study of DS-6157a in patients (pts) with advanced gastrointestinal stromal tumor (GIST).
Authors: Suzanne George, Michael C. Heinrich, Neeta Somaiah, Brian Andrew Van Tine, Robert McLeod, Abderrahmane Laadem, Ben Cheng, Satoshi Nishioka, Madan Gopal Kundu, Xiaozhong Qian, Yvonne Y. Lau, Brittany Tran, Prasanna Kumar, Ololade Dosunmu, Julia Shi, Yoichi Naito
Journal: Journal of Clinical Oncology (2022)

11512 Background: GPR20 is selectively and abundantly expressed in GISTs, the most common sarcoma of digestive tract. DS-6157a is an anti-GPR20 antibody-drug conjugate with a novel tetrapeptide-based linker and DNA topoisomerase I inhibitor exatecan derivative (DXd). The target drug-to-antibody ratio is ̃8. The DXd payload, when released, inhibits topoisomerase I and induces cell apoptosis. Methods: This study conducted in the US and Japan was designed to include a dose-escalation (Part 1) and a dose-expansion (Part 2) in adult pts with advanced GIST (NCT04276415). Part 1 evaluated safety, tolerability, efficacy, and pharmacokinetics (PK) to determine the maximum-tolerated dose (MTD) and/or recommended dose for expansion. Key eligibility criteria included ECOG PS of 0 or 1, measurable disease per RECIST v1.1, and adequate bone marrow, hepatic, and renal function. DS-6157a was administered every 3 weeks as monotherapy. Pts had tumor assessments per RECIST 1.1 every 6 weeks (wks) for 36 wks, then every 9 wks thereafter. Results: At data cutoff, 34 pts were available for full analysis: median treatment duration was 9.9 wks (range, 3-56 wks) and 5 pts (14.7%) were ongoing; median age 60.5 years (y) (range, 29-81 y); 19 pts (56%) were male; 47% of pts were Asian and 47% were white. Baseline GPR20 expression was highly prevalent, and dose-dependent PK exposure was confirmed within the range of dose levels. The MTD was 6.4 mg/kg. One pt with SDH-deficient GIST with both SDH B and NF1 mutations, had a confirmed PR with shrinkage of -75%; 18 pts (53%) experienced stable disease and 10 pts (29%) experienced progressive disease as best response. Median progression-free survival across all dose levels was 3.6 months (95% CI, 1.6, 6.9). Treatment-emergent AEs (TEAEs) occurred in all pts and treatment-related TEAEs (TRAEs) in 32 pts (94%). The most common (≥25%) all-grade (Gr) TEAEs were nausea (82%), decreased appetite (59%), fatigue (47%), anemia (44%), constipation (38%), decreased platelets (35%), and vomiting (32%). Gr ≥3 TRAEs occurred in 14 pts (41%); the most common were decreased platelets (21%) and anemia (18%). Serious TEAEs (SAEs) occurred in 9 pts (27%) and related SAEs in 4 pts (12%). Related Gr 4 SAEs in 2 pts included abnormal hepatic function, neutropenia, thrombocytopenia and leukopenia. There was 1 treatment related death (hepatic failure). Further investigations are on-going to understand the modest clinical efficacy observed. The study did not proceed to Part 2, because the data from Part 1 did not meet efficacy targets. Conclusions: DS-6157a was generally well tolerated with early signs of moderate clinical activity. While there were no objective responses in pts with KIT-mutant GIST, tumor shrinkage was observed in all 4 pts with KIT wild-type GIST treated at different doses, including a confirmed PR at the MTD in a pt with SDH-deficient GIST with both SDH B and NF1 mutations. Clinical trial information: NCT04276415.